On June 6th, 2019, the Antimicrobial Drugs Advisory Committee convened to discuss the new drug application.
On June 6th, 2019, the Antimicrobial Drugs Advisory Committee convened to discuss the new drug application (NDA) # 212862 with the sponsor company: The Global Alliance for TB Drug Development, Inc. The NDA seeks approval of pretomanid (PA-824) in combination with the antibacterial drugs bedaquiline and linezolid for the treatment of drug-resistant or intolerant tuberculosis (TB) in adults. Pretomanid is a new molecular entity derived from the nitroimidazole class of bacteriocidal drugs (the same family as the popular antibiotic metronidazole). This NDA has been designated as a priority review and the basis of approval is mainly a single-arm Phase II study: Nix-TB ( NCT02333799 ).
As of the meeting date, the study was active but enrollment had concluded with 109 patients total. A preliminary report on 45 patients along with a retrospective analysis of extensively drug-resistant TB was presented at the meeting.
In clinical studies, pretomanid did not significantly alter metabolism by the CYP3A4 enzyme, which can be considered a clinical benefit as many other anti-infective medications used in co-morbid diseases rely on the CYP3A4 enzyme. However, pretomanid was affected by other anti-infective agents that enhance or reduce the activity of the CYP3A4 enzyme. Specific combinations that must be avoided are mentioned.
Testicular and maternal toxicity were found in animal studies. Given these reproductive concerns, patients with a planned contraception were excluded and male markers of reproductive health were monitored. The development of cataracts was also noted in animal studies, so eye examinations were performed as part of the study design. Liver toxicity and seizure disorders were also cited in previous studies as a possible concern.
The Antimicrobial Drugs Advisory Committee was posed a single question: Is there substantial evidence of the effectiveness and sufficient evidence of the safety? Based on the information presented at the meeting, the panel voted in favor of pretomanid (14 YES to 4 NO). The opposition viewpoints were mainly focused on the issue of “sufficient” evidence, noting that the preliminary report with evidence from only 45 patients was not enough to satisfy that requirement. The majority who voted in favor felt that benefits of the new regimen far outweighed the known risks, pending no major changes to the outcome when the final report is released. The agency is not obligated to follow its panel’s recommendation, but normally does so.
This article cannot be considered a comprehensive clinical analysis of pretomanid and should not be used to guide patient treatment if the therapy is approved.
ISS has almost two decades of experience in developing regulatory strategies including support for FDA Advisory Committee meetings. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies. For more information on how ISS can help you prepare for your next meeting, contact email@example.com
This post was authored by Raymond Jablonski, RPh. Raymond is full-time consultant at ISS.
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